KCNQ1 Variant C122Y Detail

We estimate the penetrance of LQTS for KCNQ1 C122Y is 86%. This variant was found in a total of 1 carriers in 3 papers or gnomAD, 1 had LQTS. C122Y is not present in gnomAD. C122Y has been functionally characterized in 1 papers. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 8 individuals with LQT1 and 2 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 C122Y around 86% (9/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.35 0.988 3 0.932 97
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance density is our previously published method to calculate the average LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT1 Other Disease
32893267 2020 1 None 1 None
22949429 2012 1 None 1 None
19841300 2009 1 None 1 None
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

Functional Data Homozygously Collected

Peak current is relative to wildtype (100% being no different from wildtype). V0.5 activation is the voltages at which half of the maximal current is reached during an activation in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
30571187 HEK -4 15.1 None 0.442837464

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
30571187 HEK None None None

C122Y has 35 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. NOTE: some residues appear multiple times at different distances. This results from the fact that the functional KV7.1 channel is a homotetramer and occasionally the same residue from multiple subunits is present within the 15A window. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor Distance (Angstroms) Variants Observed in Individuals
122 0 C122Y,
119 4 G119R, G119V,
113 4
121 5
117 6 P117L,
126 6 H126D,
123 6
124 6
125 7
118 7
120 7 W120C, W120C,
114 8
112 8
110 10 V110I,
127 10 F127L, F127L, F127L,
115 10 E115A, E115G,
116 10
128 11 A128del,
109 11 R109C, R109L,
129 11 V129I,
111 11 Y111C,
243 12 R243H, R243C, R243P, R243S,
108 12 G108S,
174 12 R174H, R174C, R174L,
170 12
241 12 V241F, V241I, V241G,
130 14
244 14
173 14
177 14 S177F,
106 14
131 14
107 15 Q107H, Q107H,
242 15 D242N, D242Y,
166 15 F166V,